Depression affects approximately 14 million people in the United States and 340 million people worldwide, making it one of the leading causes of disability [Kessler R C. Et al., JAMA, 2003, 289, 3095-3105]. Depression is also associated with high rates of relapse, recurrence, disability, and death [Hirschfield R M., et al., JAMA, 1997, 277, 333-340; Keller M B., J. Psychopharmacol. 1996, 10(suppl 1); 41-44].
The role of serotonin in the treatment of depressive and anxiety disorders is underscored by the therapeutic action of selective 5-HT reuptake inhibitors acting to enhance the degree of activation of various 5-HT receptor subtypes [Blier P. and Ward M., Biol. Psychiatry, 2003, 53, 193-203]. Selective serotonin reuptake inhibitors (SSRIs) have had significant success in treating depression and related disorders and have become among the most prescribed drugs since 1980s. But, the use of SSRIs leads to the indiscriminate activation of all serotonin receptors and it can be understood as undesirable actions of serotonin in undesirable pathways at undesirable receptor subtypes [Stahl S M., 2008, Essential Psychopharmacology (3rd ed.), 531]. Although there are various treatment options for depressive and anxiety disorders, a need still exists for new drugs with improved tolerability and adequate efficacy.
In contrast to the SSRIs, the 5-HT1A agonist or partial agonist acts directly on postsynaptic serotonin receptors to increase serotonergic neurotransmission. And, the 5-HT1A partial agonists, Buspirone and Gepirone [Robinson D S., et al., J. Clin. Psychopharmacol., 1990, 10(3), 67S-76S; Bielski R J., J. Clin. Psychiatry, 2008, 69(4), 571-577], and 5-HT1A agonist, Flexinoxan [Grof P., International Clin. Psychopharmacology, 1993, 8(3), 167-172], have shown efficacy in clinical trials for the treatment of depression. Moreover, because of their unique pharmacological profile, 5-HT1A agonists possess theoretic advantages in the treatment of major depression relative to other classes of antidepressants. In particular, these drugs are not expected to produce weight gain, sedation, or sexual dysfunctions, which are often encountered with some of the antidepressants introduced in the last 10 years [Blier P. and Ward M., Biol. Psychiatry, 2003, 53, 193-203].
Many reports have disclosed that phenyl piperazine compounds are effectively used for controlling depression and anxiety.
For example, U.S. Pat. No. 5,578,596 discloses that the 2-alkoxy-5,6,7,8-tetrahydroquinoxaline derivatives have a strong affinity for serotonin 1A receptor and are useful for preventing and treating serotonergic neuron-related disease.
These compounds are found to be very effective as therapeutical medicines for managing depression and anxiety.
Active research and development efforts have continued to be directed to the application of phenyl piperazine compounds for the treatment of depression and anxiety.